P1472: INTERIM RESULTS OF SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS FROM AN ONGOING OPEN-LABEL STUDY INVESTIGATING FTX-6058 IN ADULTS LIVING WITH SICKLE CELL DISEASE
Authors: P. Bruno, J. Kanter, J. Ziegler, B. Stuart, J. Ahn, J. Dunn, G. Allen, C. Morabito
Journal: HemaSphere (2022)

Background: FTX-6058 is a potent and selective oral small-molecule inhibitor of Embryonic Ectoderm Development (EED) that has demonstrated robust fetal hemoglobin (HbF) protein expression in cell and murine models of Sickle Cell Disease (SCD). SCD is a genetic disorder of the red blood cells caused by a mutation in the HBB gene, which results in red blood cell sickling, hemolysis, vaso-occlusive crises (VOCs), and other complications. HbF (α2γ2) prevents the pathologic polymerization of HbS in deoxygenated environments. Individuals with SCD who also have hereditary persistence of HbF (HPFH) have attenuated pathology and may present as asymptomatic when HbF levels are >25%. HPFH provides genetic and clinical evidence that increasing HbF has the potential to prevent or reduce disease-related pathophysiology, including hemolysis, pain, and VOCs. Preclinically, FTX-6058 has demonstrated increases in HbF levels up to approximately 40% of total hemoglobin, which has the potential to positively impact important clinical outcomes in SCD. Clinically, multiple ascending dose (MAD) data from a Phase 1, randomized, double-blind, placebo-controlled study of FTX-6058 in healthy volunteers demonstrated robust target engagement (H3K27me3 reduction) and potent induction of HBG (hemoglobin subunit γ) mRNA, translation of which is required for HbF expression. Aims: To share interim results from the ongoing open-label study investigating FTX-6058 in adults living with SCD. Methods: The ongoing Phase 1b open-label study investigating FTX-6058 is a multiple cohort trial that is being conducted in adults with SCD +/- hydroxyurea. In the first cohort, up to 10 volunteers will receive FTX-6058 6 mg once daily orally for 4 weeks. Eligible volunteers may choose to continue dosing for an additional 8 weeks at the same dose via an extension study. Up to two additional cohorts with doses selected between 2 – 20mg inclusive may be added to the study. The primary endpoints of the study are the safety and tolerability of FTX-6058 as measured by the frequency of adverse events and the pharmacokinetic profile of FTX-6058 in subjects with SCD. Secondary and exploratory endpoints include the effect of FTX-6058 on HbF induction in peripheral blood and other relevant SCD biomarkers and clinical endpoints. Results: To date, FTX-6058 has been evaluated in 7 healthy volunteer (HV) SAD cohorts (2 to 60 mg), 5 HV MAD cohorts (2 to 30 mg QD, 14-day dosing), and an open-label food-effect cohort. Treatment-related adverse events have been mild (Grade 1 or 2) and resolved. There have been no SAEs or discontinuations. PK profiles have demonstrated dose proportionality across all doses. Robust target engagement was observed across the entire dose range in the MAD cohorts. Additionally, exposures achieved in the 6 – 30mg MAD cohorts resulted in dose-proportional 2.4 – 6.2 fold placebo-adjusted increases from baseline in HBG mRNA and no decrease in HBB mRNA. Safety, tolerability, pharmacokinetics, and pharmacodynamics data from the ongoing, open-label trial in adults with SCD will be presented. In people with SCD, measurable increases in HbF (HPLC) may be observed by 4 weeks and may achieve near-maximal levels by 12 weeks. Pharmacodynamic reporting will focus on HbF changes. Summary/Conclusion: FTX-6058 is an investigational, potential first-in-class oral HbF inducer. To date, FTX-6058 has demonstrated favorable safety and tolerability profile, with PK linearity and time- and dose-dependent increases in HBG mRNA that support longer term dosing in people living with SCD.